Interestingly, gene sets previously implicated in SCZ (i.e., post-synaptic density (PSD) proteins, voltage-gated calcium channels (VGCCs), and fragile X mental retardation protein (FMRP) targets) were found significantly enriched in genes carrying IBD<sub>risk</sub> variants.
We also found that many of the diverse gene sets previously associated with schizophrenia (genes involved in synaptic function, those encoding mRNAs that interact with FMRP, antipsychotic targets, etc.) generally implicated the same brain cell types.
Notably, Top3β proteins bearing point mutations from schizophrenia and autism individuals are defective in association with FMRP; whereas one of the mutants is also deficient in binding mRNAs, catalyzing RNA topoisomerase reaction, and promoting synapse formation.
This gene-set has also been linked to Schizophrenia suggesting that FMRP-targeted transcripts might be involved in a general mechanism with shared genetic etiology between psychiatric disorders.
FMRP targets and postsynaptic density genes, each implicated in schizophrenia, were significantly overrepresented among differentially expressed genes (DEGs).
Pathways implicated in schizophrenia were upregulated in the 48 h findings (major histocompatibility complex, synapses, FMRP interacting RNAs and calcium channels).
A major research priority has been the identification of the mRNA targets of FMRP, particularly as recent studies suggest an excess of FMRP targets among genes implicated in idiopathic autism and schizophrenia.
LGD targets in the joint class overlap with published targets for intellectual disability and schizophrenia, and are enriched for chromatin modifiers, FMRP-associated genes and embryonically expressed genes.
We observed multiple statistically significant mRNA and protein changes in levels of GABRθ, GABRρ2, mGluR5 and FMRP molecules including concordant reductions in mRNA and proteins for GABRθ and mGluR5 in lateral cerebella of subjects with schizophrenia; for increased mRNA and protein for GABRρ2 in lateral cerebella of subjects with bipolar disorder; and for reduced mRNA and protein for mGluR5 in BA9 of subjects with bipolar disorder.
These results raise the possibility of impaired translation of FMR1 mRNA, altered epigenetic regulation, or increased degradation of FMRP in schizophrenia, which may play a role in dysfunctional neurodevelopmental processes and impaired neuroplasticity.
We observed multiple statistically significant mRNA and protein changes in levels of GABRθ, GABRρ2, mGluR5 and FMRP molecules including concordant reductions in mRNA and proteins for GABRθ and mGluR5 in lateral cerebella of subjects with schizophrenia; for increased mRNA and protein for GABRρ2 in lateral cerebella of subjects with bipolar disorder; and for reduced mRNA and protein for mGluR5 in BA9 of subjects with bipolar disorder.
These results raise the possibility of impaired translation of FMR1 mRNA, altered epigenetic regulation, or increased degradation of FMRP in schizophrenia, which may play a role in dysfunctional neurodevelopmental processes and impaired neuroplasticity.
We conclude that although mutations within the FMR-1 gene do not have a major aetiological role in schizophrenia in our collection of pedigrees, it is possible that FMR-1 mutations can modify the clinical phenotype of schizophrenia.
Patients diagnosed using DSM-III-R criteria as having schizophrenia and other related disorders (n = 128) were assessed for CGG trinucleotide repeat expansion in the fragile X mental retardation 1 (FMR-1) gene.